Sympathetic neuronal activity regulates such cardiovascular variables as heart rate, arterial blood pressure and myocardial contractility. The excitability of sympathetic neurons is determined in large part by a conductance known as the M-current. These investigators have recently determined that the M-current is encoded by the KCNQ2 and KCNQ3 genes. Increased understanding of these genes is a prerequisite to further investigation of 1) how the M-current is regulated during sympathetic activity, 2) the developmental control of this current and 3) the targeting of the M-current, and the pathways involved in its regulation, for pharmacological interventions in cardiovascular pathologies. The overall goal of the present application is to understand at a molecular level the subunit interactions that generate the constituent channels of the M-current. The projects outlined in Specific Aim 1 use knock-out and gain-of-function experiments to confirm our hypothesis that the M-current of sympathetic neurons is encoded by KCNQ2 and KCNQ3. Specific Aim 2 would test the hypothesis that the formation of the M-current involves protein interaction between the KCNQ2 and KCNQ3 subunits. Specific Aim 3 would test the corollary that protein interaction between the subunits facilitates the movement of subunit proteins from the endoplasmic reticulum to the cell membrane. Specific Aim 4 would test the hypothesis that specific splice variants of the KCNQ2 and KCNQ3 genes encode the M-channel of sympathetic neurons.